Polycomb repressive complex 2 binds and stabilizes NANOG to suppress differentiation-related genes to promote self-renewal

Da-Wei Yeh; Cheng Liu; Juan Carlos Hernandez; Stanley M Tahara; Hidekazu Tsukamoto; Keigo Machida

doi:10.1016/j.isci.2023.107035

Polycomb repressive complex 2 binds and stabilizes NANOG to suppress differentiation-related genes to promote self-renewal

iScience. 2023 Jun 7;26(7):107035. doi: 10.1016/j.isci.2023.107035. eCollection 2023 Jul 21.

Authors

Da-Wei Yeh¹, Cheng Liu¹, Juan Carlos Hernandez¹, Stanley M Tahara¹, Hidekazu Tsukamoto^{2

3}, Keigo Machida^{1

3}

Affiliations

¹ Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA.
² Department of Pathology; University of Southern California, Los Angeles, CA 90033, USA.
³ Southern California Research Center for ALPD and Cirrhosis, Los Angeles, CA 90033, USA.

Abstract

The synergistic effect of alcohol and HCV mediated through TLR4 signaling transactivates NANOG, a pluripotency transcription factor important for the stemness of tumor-initiating stem-like cells (TICs). NANOG together with the PRC2 complex suppresses expression of oxidative phosphorylation (OXPHOS) genes to generate TICs. The phosphodegron sequence PEST domain of NANOG binds EED to stabilize NANOG protein by blocking E3 ligase recruitment and proteasome-dependent degradation, while the tryptophan-rich domain of NANOG binds EZH2 and SUZ12. Human ARID1A gene loss results in the resistance to combined FAO and PRC2 inhibition therapies due to reduction of mitochondrial ROS levels. CRISPR-Cas9-mediated ARID1A knockout and/or constitutively active CTNNB1 driver mutations promoted tumor development in humanized FRG HCC mouse models, in which use of an interface inhibitor antagonizing PRC2-NANOG binding and/or FAO inhibitor blocked tumor growth. Together, the PRC2-NANOG interaction becomes a new drug target for HCC via inducing differentiation-related genes, destabilizing NANOG protein, and suppressing NANOG activity.

Keywords: Molecular physiology; Stem cells research.

Abstract

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